The NCT05693982 trial is a Phase 2 clinical study evaluating ASN90, an oral O-GlcNAcase (OGA) inhibitor developed by [Asceneuron](/companies/asceneuron), in patients with early Alzheimer's disease[@asn90_trial]. This trial represents one of three active OGA inhibitor Phase 2 programs (alongside FNP-223 in PSP and LY-3372689 in AD/PSP).
Trial Details
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ASN90 Phase 2 Trial (NCT05693982)
Overview
Mermaid diagram (expand to render)
The NCT05693982 trial is a Phase 2 clinical study evaluating ASN90, an oral O-GlcNAcase (OGA) inhibitor developed by [Asceneuron](/companies/asceneuron), in patients with early Alzheimer's disease[@asn90_trial]. This trial represents one of three active OGA inhibitor Phase 2 programs (alongside FNP-223 in PSP and LY-3372689 in AD/PSP).
Trial Details
| Parameter | Value | |-----------|-------| | Trial ID | NCT05693982 | | Phase | Phase 2 | | Status | Ongoing (as of early 2026) | | Drug | ASN90 | | Company | Asceneuron (Lausanne, Switzerland) | | Indication | Early Alzheimer's Disease (MCI due to AD, mild AD dementia) | | Enrollment | ~150 patients | | Duration | 52 weeks treatment + 26-week follow-up | | Primary Endpoints | Safety, tolerability, biomarker changes | | Secondary Endpoints | Cognitive measures (ADAS-Cog14, ADCS-MCI-ADL), CSF tau biomarkers |
Study Design
Population
Early AD patients (MCI due to AD or mild AD dementia)
Secondary: CSF p-tau181, p-tau231, total tau, cognitive measures
Mechanism: OGA Inhibition
ASN90 inhibits O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc modifications from proteins including tau[@oga_mechanism][@ogcnacylation]:
Increased tau O-GlcNAcylation competes with pathological phosphorylation at the same serine/threonine sites
Reduced tau phosphorylation at key epitopes (Thr231, Ser396, Ser400)
Decreased tau aggregation and neurofibrillary tangle formation
The Yin-Yang Hypothesis
ASN90 operates on the yin-yang relationship between O-GlcNAcylation and phosphorylation:
| Modification | Effect on Tau | Disease State | |--------------|--------------|---------------| | O-GlcNAcylation | Protective (blocks phosphorylation) | Reduced in AD brain | | Phorylation | Pathological (promotes aggregation) | Elevated in AD brain |
By inhibiting OGA, ASN90 shifts the balance toward protective O-GlcNAcylation.
Biomarker Strategy
Target Engagement Biomarkers
CSF O-GlcNAc levels: Direct measurement of O-GlcNAcylation as pharmacodynamic marker
Blood O-GlcNAc: Peripheral blood mononuclear cell O-GlcNAc as accessible alternative
Disease Progression Biomarkers
CSF p-tau181: Phosphorylated tau at Thr181
CSF p-tau231: Phosphorylated tau at Thr231 (correlation with tangle burden)
CSF total tau: Overall tau protein turnover
NfL: Neurofilament light chain for neurodegeneration
Amyloid/Tau Co-Pathology
The trial enrolls patients with:
Confirmed amyloid pathology (required for inclusion)
Elevated tau biomarkers (evidence of co-pathology)
This represents a more complex patient population than pure tauopathies
Comparison with Other OGA Inhibitor Trials
| Trial | Drug | Company | Indication | Phase | Key Difference | |-------|------|---------|------------|-------|---------------| | NCT05693982 | ASN90 | Asceneuron | Early AD | Ongoing | | NCT05063539 | LY-3372689 | Eli Lilly | AD | Completed (no cognitive benefit) | | NCT05682807 | LY-3372689 | Eli Lilly | PSP | Pure tauopathy | | NCT05649734 | FNP-223 | Ferrer | PSP | Pure tauopathy, larger cohort |
Key Distinctions
AD vs PSP: ASN90 targets AD (mixed amyloid-tau pathology), while FNP-223 targets PSP (pure 4R-tauopathy)
Chemical class: ASN90 is a thienopyrimidine (different from LY3372689's pyrrolopyrimidine)
Brain penetration: ASN90 claims higher brain-to-plasma ratio
Selectivity: ASN90 has >1000-fold OGA/OGT selectivity
Clinical Program Context
Preclinical Foundation
ASN90 demonstrated in preclinical studies:
Low nanomolar OGA potency (IC50 ~2 nM)
>1000-fold selectivity over OGT (O-GlcNAc transferase)
Dose-dependent brain O-GlcNAc increase in mice
Reduced tau phosphorylation at pathogenic sites
Phase I Results
The preceding Phase I trial (NCT05463754) established:
Safety and tolerability in healthy volunteers
Pharmacokinetics supporting once-daily dosing
CSF O-GlcNAc engagement at doses 10-50 mg
No significant adverse events at tested doses
Challenges and Considerations
Biomarker-to-Outcome Gap
The OGA inhibitor field (including LY3372689 MAGNOLIA) has demonstrated:
✓ Target engagement (CSF O-GlcNAc increases)
? Clinical cognitive benefit
This highlights the challenge of translating mechanism to clinical outcome in AD.
Amyloid Co-Pathology
A key question is whether ASN90 can show benefit in AD where:
Amyloid pathology may drive cognitive decline independently
Tau pathology may be too advanced by time of intervention
Combination with anti-amyloid therapy may be needed
PSP as Cleaner Readout
This context makes the parallel PSP trials (FNP-223 PROSPER, LY3372689 LOTUS) important - they test OGA inhibition in pure tauopathies without amyloid co-pathology.
[O-GlcNAcylation in tauopathy (Nature Reviews Neurology, 2023)](https://doi.org/10.1038/s41582-023-00765-4)
Pathway Diagram
The following diagram shows the key molecular relationships involving ASN90 Phase 2 Trial - Early Alzheimer's Disease (NCT05693982) discovered through SciDEX knowledge graph analysis: